Structural analysis of spiro beta-lactone proteasome inhibitors.
Spiro beta-lactone-based proteasome inhibitors were discovered in the context of an asymmetric catalytic total synthesis of the natural product (+)-lactacystin (1). Lactone 4 was found to be a potent inhibitor of the 26S proteasome, while its C-6 epimer (5) displayed weak activity. Crystallographic studies of the two analogues covalently bound to the 20S proteasome permitted characterization of the important stabilizing interactions between each inhibitor and the proteasome's key catalytic N-terminal threonine residue. This structural data support the hypothesis that the discrepancy in potency between 4 and 5 may be due to differences in the hydrolytic stabilities of the resulting acyl enzyme complexes.
Groll
Michael
M
Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany.
Balskus
Emily P
EP
Jacobsen
Eric N
EN
D018360:Crystallography, X-Ray; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D061988:Proteasome Inhibitors; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology
D007783:Lactones; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D013141:Spiro Compounds; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease